Can CT or MRI volumetry substitute scintigraphy in living kidney donor evaluation? A systematic review

Background Current potential living kidney donor’s assessment includes functional and anatomical evaluation. Scintigraphy is recommended in some cases and some centers include this test in the donor’s protocol. Recent studies advocate for the avoidance of this test as CT or MRI volumetry showed to accurately assess donor’s renal function. Objective To summarize scientific evidence on image tests for pre-donation and/or post-nephrectomy renal function evaluation. Evidence acquisition This review followed the guidelines set by the European Association of Urology and adhered to PRISMA 2020 recommendations. The protocol was registered in PROSPERO on 10th December 2022 (ID: CRD42022379273). Evidence synthesis Twenty-one studies met the inclusion criteria after thorough screening and eligibility assessment. According to QUADAS-2, patient selection and flow/timing domains showed a predominant low risk of bias. The correlation between split renal function (SRF) using CT and scintigraphy varied from weak (r = 0.21) to remarkably strong (r = 0.949). Bland–Altman agreement demonstrated moderate to excellent results, with mean differences ranging from -0.06% to 1.76%. The correlation between split renal volume (CT) and estimated glomerular filtration rate (eGFR) at 6 months or 1 year after nephrectomy showed a moderate correlation, with coefficients ranging from 0.708 to 0.83. The correlation between SRF (MRI) and renal scintigraphy reported a moderate correlation, with correlation coefficients of 0.58 and 0.84. MRI and scintigraphy displayed a good agreement, with a 66% agreement observed and mean differences of ± 0.3%. Conclusions Despite study heterogeneity, MRI or CT-based renal volumetry appears promising compared to scintigraphy, with favorable correlations and agreement. Supplementary Information The online version contains supplementary material available at 10.1007/s00345-024-05024-y.


Introduction
Living donor kidney transplantation (LDKT) is the most valuable source of organs for kidney transplantation (KT) worldwide.It has been promoted during the last decades as a crucial strategy to increase the number of organs and try to reach the increasing demand.In addition, LDKT has demonstrated superior outcomes in terms of organ survival, morbidity, and mortality compared to cadaveric donor KT [1].This could be related to the shorter waiting time (or even the avoidance of dialysis) and the better quality of the organs with reduced ischemia time.
Living kidney donor needs a multidisciplinary evaluation to ensure that neither the donor nor the recipient assume excessive risks with the interventions.Historically, preoperative donor work-up includes renal function (creatinine clearance) and anatomical assessment (CT angiography).However, the SRF (defined as the proportion of total RF contributed by each kidney) should be measured by combining 51Cr EDTA and 99mTc DMSA in concrete occasions, such as when there is a size disparity between the two kidneys, the renal function (RF) is close to the acceptable threshold for the donation, or there is anatomical abnormality or complexity [2].Moreover, to assess the potential donor's RF carefully, some centers protocols include performing both imaging tests (CT and scintigraphy).In contrast, recent studies advocate for the avoidance of renal scintigraphy and instead suggest CT or MRI volumetry, as non-invasive, easy-to-perform, resource-saving, and reliable alternatives.Different studies indicate that predonation renal volumetry could accurately assess SRF and post-donation kidney function (PDKF).Cohort studies in healthy patients with an average glomerular filtration rate have demonstrated that renal volume is very similar in both kidneys [3][4][5][6].Despite these promising results, there is still lack of evidence regarding the most appropriate preoperative differential RF assessment for kidney donor candidates.
To fill this gap, we conducted a systematic review of the available scientific evidence pertaining to imaging modalities for pre-donation RF evaluation of potential donors and/ or for the PDKF evaluation.

Evidence acquisition
This systematic review was conducted following the principles highlighted by the European Association of Urology guidelines [7] and following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 recommendations [8].The protocol was registered in the International Prospective Register of Ongoing Systematic Reviews (PROSPERO; http:// www.crd.york.ac.uk/ prosp ero) on 10th December 2022 (ID:CRD42022379273).

Search strategy
A systematic literature screening was conducted by two authors (ALA and TP) using the Cochrane Library, MED-LINE/Pubmed and Embase databases.The search was limited to articles published in the English language between January 2000 and January 2023.The search strategy incorporated both free-text and MeSH terms (Appendix 1).Furthermore, the reference lists of the initially selected articles were manually scrutinized to identify additional studies of relevance.The final list of selected articles underwent comprehensive review and approval by all co-authors.

Inclusion and exclusion criteria
A specific population (P), intervention (I), comparator (C), outcome (O), and study design (S) (PICOS) framework was assessed to define the study eligibility.
The PICOS framework for this review was as follows: -

Study selection and data extraction
Two members of the research team (ALA and TP) independently conducted a systematic search of the previous mentioned databases, following the PICOS framework as listed.The screening of titles and abstracts was performed using Rayyan (Rayyan Systems, Cambridge,MA, USA).Subsequently, the full texts of the remaining studies were examined by all co-authors after the exclusion process.Data extraction was carried out using a pre-defined spreadsheet developed in advance and managed by two members of the team (ALA and TP).In instances where discrepancies arose regarding study selection or data extraction, resolution was achieved by another author (RC).
The following data were extracted for each study: • Study identification: authors, publication year, country.

Risk of bias (RoB) assessment
RoB assessment was performed independently by two authors (ALA and TP) using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2) [9].QUADAS-2 tool was used to assess the RoB over four domains, patient selection, index test(s), reference standard and flow and timing.The disagreement was solved by a third party (RC).

Data synthesis
The methodological and clinical heterogeneity of the included studies implied that meta-analysis was inappropriate.Therefore, a narrative synthesis of the data was performed.The primary outcomes of interest pertained to the comparison of SRF between the different tests.Additionally, secondary outcomes focused on the evaluation of PDKF.

Literature search and study characteristics
The literature search initially included 695 papers.After screening and eligibility assessment, twenty-one studies met the inclusion criteria (Fig. 1).
Only three of the studies included were prospective design [3,10,11].The samples sizes varied considerably, ranging from 12 patients [12] to 835 patients [13].Furthermore, the timeframe for the included cohorts varied widely, ranging from 1997-2001 [14] to 2017-2020 [11].A comprehensive breakdown of the main characteristics of the included studies is provided in Table 1.
Regarding the imaging modalities, three studies reported results from MRI [3,10,15] while eighteen from CT.As part of the inclusion criteria, all the studies compare their main outcomes with the gold standard, scintigraphy.Each included study underwent a correlation and agreement analysis between the two tests comparing SRF and/or PDKF.In addition, eight studies evaluate RF at 6 months or 1 year after surgery [12,13,[16][17][18][19][20][21].

CT vs scintigraphy SRF outcomes
The SRF correlation between CT and scintigraphy was assessed in 94.44% (17/18) of the studies.The correlation exhibited considerable variability, spanning from studies that reported a weak correlation (r = 0.21 [22]) to those demonstrating a remarkably strong correlation (r = 0.949 [17]).However, when considering the individual  kidney comparison, the observed correlations improved significantly, ranging from 0.52 [23] to 0.955 [11].Bland-Altman agreement was calculated in 72.22% (13/18) of the studies and found to be moderate to excellent, from a mean of −0.06% [24] to 1.76% [13].Notably, Lal et al. demonstrated a perfect agreement of 0% in the individual comparison between the right and left kidney [11].

SRF outcomes
The SRF correlation between MRI and renal scintigraphy was evaluated in 66.67% (2/3) of the comparative studies.The findings indicated a moderate correlation in both studies, with correlation coefficients of 0.58 and 0.84, respectively [10,15].
Regarding the agreement analysis, different approaches were employed.One study utilized a plot method for evaluation, which proved challenging due to the absence of means and cut-offs provided by the authors [10].In contrast, the other two studies applied the "agreement observed" between the two tests [15] and the Bland-Altman test [3].These latter methods showed good agreement between MRI and scintigraphy, with a 66% agreement observed and mean differences of −0.3% in the right kidney and 0.3% in the left kidney, respectively.

PDKF outcomes
In the studies included, there was no assessment of correlation with PDKF.

RoB assessment and generalizability
RoB was evaluated according to QUADAS-2 assessment tool, as shown in Fig. 2 and Supplementary Table 1.This tool revealed a predominant low RoB in patient selection and flow and timing domains and a majority low concern of applicability in all the domains studied.Only four studies [12,[24][25][26] indicated that the outcomes were blinded for the researchers or radiologists.
In three studies [18,20,21] the authors not only assessed living donors but also collected data on recipients.Nonetheless, the outcomes of donors and recipients were reported separately, allowing for a thorough and independent analysis of each group.

Discussion
Donor's evaluation is fundamental both for the receipt and the donor.In addition to anatomy and compatibility considerations, the potential donor's assessment must prioritize the minimization of both short and long-term risks associated with nephrectomy.It is important to emphasize that donors are healthy individuals, willingly undergoing a nephrectomy, which is a high-risk surgical procedure [27], driven by altruistic intentions to "gift" their kidney, often to a relative.
There is an active debate on the donor's optimal study pre-donation as recent studies support the option of performing only a volumetry test which can assess SRF and even PDKF instead of the actual (but not universalized) functional and anatomical evaluation or scintigraphy and CT.
Unfortunately, the availability of literature on SRF assessment through imaging tests remains limited, with only twenty-one studies being included in this review.Summarizing outcomes proved challenging due to the heterogeneity observed among the included studies, mainly concerning the methods employed for study design, scintigraphy tracer, CT characteristics, and statistical analysis.This heterogeneity rendered meta-analysis unfeasible.Furthermore, the absence of an established consensus makes direct comparisons arduous.Despite these challenges, the QUADAS-2 assessment revealed an acceptable RoB (Fig. 2).
Focusing on scintigraphy tracers, the studies included in this review used different agents, such as DTPA, MAG3, and DMSA, sometimes even within the same study [21,26].The choice of the radiopharmaceutical was dependent on the type of renal scan performed [30].DTPA and MAG3 have proven useful in measuring GFR and evaluating flow through the pyelocalyceal system and bladder.These tracers are typically employed for dynamic imaging, while DMSA is primarily used for static imaging and cortical anatomy assessment, particularly for pathologies like renal ectopia or renal scarring [30].There is currently lack of scientific evidence published on the optimal nuclear tracer for evaluating RF in a healthy population, such as potential kidney donor.Consequently, we can only speculate that the results obtained from different tracers yield similar outcomes.However, it is crucial to acknowledge that no concrete evidence supports this hypothesis.
In terms of CT characteristics, the studies reviewed employed various techniques (such as multidetector, conventional, and CT angiography), thickness (from 0.5 [4] to 5 mm [28]), and volume reconstruction calculation methods (automatic 3D reconstruction, area multiplied by thickness, modified ellipsoid…).This diversity complicates direct comparisons between studies.Regarding CT thickness, recent studies have yielded similar findings in assessing kidney volume, demonstrating low interobserver variability [29].Focusing on volume reconstruction, there is currently no consensus on the method for the calculation of renal volumetry.
Our review revealed robust correlations between CT and scintigraphy, with good correlation coefficients ranging from 0.9 to 1 [14,17,21,28], contrasting with Wahba et al. [20] lower correlations rate.Notably, these correlations held validity across studies with both small and large cohort populations, as evidenced in smaller studies [14,28] compared those with larger cohort populations [17,21].Moreover, the correlation between MRI and scintigraphy also demonstrated favorable results, with a coefficient of 0.84 reported in the study conducted by Artunc et al. [10].
Regarding the agreement between tests, CT studies consistently showed the best correlations, as shown by the findings of different studies [11,24,26,28].Another small cohort study [3] also obtained excellent agreement between MRI and scintigraphy.Nevertheless, it is important to note that this level of agreement was not consistently observed in other MRI studies, particularly those with larger cohort populations [15].
The main limitation of this systematic review stems from the substantial heterogeneity observed in the literature due to the lack of robust evidence.However, these limitations serve as an initial catalyst for enhancing awareness and prompting improvements in study design, ultimately benefiting decision-making and diagnostic practices.Despite these challenges, our review demonstrated an acceptable RoB.Nevertheless, our systematic review provides valuable insights into the current state of evidence concerning imaging tests for assessing kidney function in potential donors.

Conclusions
Living donor nephrectomy holds significant importance for clinicians, patients, their families, and transplant surgeons alike.However, the current state of evidence is marred by a notable lack of robust data, presenting a significant challenge to informed decision-making in clinical practice.Nevertheless, promising results have emerged from studies assessing renal volumetry through MRI or CT demonstrating favorable correlation and agreement compared to the established gold standard, scintigraphy.It is imperative to prioritize improvements in study design and initiate prospective registries dedicated to this area.Our systematic review represents the first step to acknowledge these limitations and pave the way for multidisciplinary prospective studies involving nephrologists and urologists.

Fig. 1 1
Fig. 1 Flowchart showing the literature search and systematic review process according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement recommendations

Fig. 2
Fig. 2 Overview of the overall risk of bias and applicability judgements for the studies included in the review according to the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2)